The present invention relates to 4-hydroxy-4-phenylpiperidine derivatives excellent in peripheral analgesic action or salts thereof; and pharmaceuticals containing the same.
As an analgesic, known are central opioid analgesics typified by morphine, non-steroidal anti-inflammatory drugs (NSAIDS) typified by indomethacin and local anesthetics typified by lidocaine [The Journal of Medicinal Chemistry, 42(9), 1481(1999) and cited references described therein].
Morphine however cannot be used freely because of its undesirable central side effects. In addition, there are pains against which neither non-steroidal anti-inflammatory drugs nor local anesthetics have sufficient analgesic effects. There is accordingly a demand for the development of a medicament which is safer and has higher analgesic effects than them.
In recent years, existence of a xcexc-receptor at the periphery has been revealed and analgesic action via this receptor has come to be elucidated [The Journal of Pharmacology and Experimental Therapeutics, 248(3), 1269(1989); The Journal of Investigative Dermatology, 111, 297(1988); and Drug Therapy, 323, 1685(1995)].
In Japanese Patent Application Laid-Open No. Sho 47-173, described are diarylpiperidinobutylamide compounds and among them, loperamide developed as a stegnotic is under development as a peripheral analgesic [Anesthesiology, 90, 225(1999); The Journal of Pharmacology and Experimental Therapeutics, 289, 494(1999)].
The peripheral analgesic action of loperamide is however not always satisfactory.
An object of the present invention is therefore to provide a compound excellent in peripheral analgesic action.
With the foregoing in view, the present inventors have carried out an extensive investigation to obtain a compound having excellent peripheral analgesic action. As a result, it has been found that a 4-hydroxy-4-phenylpiperidine derivative represented by the below-described formula (1) is markedly superior to the above-described loperamide in peripheral analgesic action and is therefore useful as a medicament, leading to the completion of the present invention.
In one aspect of the present invention, there is thus provided a 4-hydroxy-4-phenylpiperidine derivative 
represented by the following formula (1):
[wherein, R1 and R2 are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R1 and R2 may form a heterocyclic group together with the adjacent nitrogen atom, R3 represents a hydrogen atom or a group xe2x80x94(CR4R5)nxe2x80x94Y (in which, R4 and R5 each represents a hydrogen atom or a lower alkyl group, Y represents a group xe2x80x94COOR6, xe2x80x94CONR7R8, xe2x80x94OR9 or xe2x80x94OCOR10 (in which R6, R9 and R10 each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, R7 and R8 are the same or different and each independently represents a hydrogen atom, a lower alkyl group or a cycloalkyl group or R7 and R8 may form a heterocyclic ring together with the adjacent nitrogen atom), and n stands for 1 to 6)], or salt thereof; and a medicament containing it or its salt as an effective ingredient.
In another aspect of the present invention, there is also provided a pharmaceutical composition containing the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof and a pharmaceutically acceptable carrier.
In a further aspect of the present invention, there is also provided use of the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof as a medicament.
In a still further aspect of the present invention, there is also provided a paint treating method, which comprises administering the above-described 4-hydroxy-4-phenylpiperidine derivative or salt thereof.
Examples of the lower alkyl group as R1 or R2 in the formula (1) of the invention compound (1) include linear or branched C1-6 alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As the cycloalkyl group, C3-8 ones are preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Among them, hydrogen atom and C1-6 alkyl groups are particularly preferred as each of R1 and R2.
The number of the member of the heterocyclic ring formed by R1 and R2 together with the adjacent nitrogen atom is preferably 5 to 8. Examples of such a ring include pyrrolidine, piperidine, piperazine and morpholine rings, of which the pyrrolidine ring is particularly preferred.
Examples of the lower alkyl group as R4 or R5 include linear or branched C1-6 alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As R4 or R5, a hydrogen atom is preferred.
Examples of the lower alkyl group as R6, R7, R8, R9 or R10 include linear or branched C1-6 alkyl groups, more specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups. As the cycloalkyl group, C3-8 ones are preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The number of the member of the heterocyclic ring formed by R7 and R8 together with the adjacent nitrogen atom is 5 to 8. Examples of such a ring include pyrrolidine, piperidine, piperazine and morpholine rings. As R6, hydrogen atom and C1-6 alkyl groups (particularly, ethyl) are preferred, while as R9, hydrogen atom and C1-6 alkyl groups (particularly, methyl) are preferred. As R10, C1-6 alkyl groups, particularly, methyl group is preferred. n stands for 1 to 6, of which 1 to 3 is preferred.
No particular limitation is imposed on the salt of the invention compound (1) insofar as it is a pharmaceutically acceptable salt thereof. Examples include addition salts of an inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid and addition salts of an organic acid such as formic acid, acetic acid, fumaric acid, maleic acid or tartaric acid. The invention compounds also embrace solvates such as hydrates.
Each of the 4-hydroxy-4-phenylpiperidine derivatives and salts thereof according to the present invention can be prepared, for example, by any one of the following (Process A) to (Process C).
(Process A) 
[wherein, X represents a halogen atom, and R1 and R2 have the same meanings as described above].
Described specifically, Invention compound (1a) is available by reacting Compound (1) with Compound (2). This reaction is usually conducted in the presence of 2 to 5 equivalents, preferably 3 equivalents of a base at 40 to 100xc2x0 C., preferably 50 to 60xc2x0 C. for 1 to 3 hours. This reaction can be conducted in an anhydrous solvent such as benzene, toluene, tetrahydrofuran or dimethylformamide. Examples of the base include inorganic bases such as sodium carbonate and sodium hydroxide and organic bases such as triethylamine.
Each of Compound (1) and Compound (2) can be synthesized in a known manner.
(Process B) 
[wherein, n stands for 1 to 6, and R1, R2, R4, R5, X and Y have the same meanings as described above].
Described specifically, Invention compound (1b) is available by reacting Compound (1a) with Compound (3). This reaction is usually conducted in the presence of 1 to 3 equivalents, preferably 1 to 1.5 equivalents of a base at 20 to 100xc2x0 C., preferably 20 to 60xc2x0 C. for 2 to 36 hours. This reaction can be conducted in an anhydrous solvent such as acetone, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Examples of the base include inorganic bases such as sodium carbonate, sodium hydroxide and sodium hydride and organic bases such as triethylamine. The base may be added together with potassium iodide.
Compound (3) is commercially available as a reagent easily or can be synthesized in a known manner.
(Process C) 
[wherein, R1, R2 and n have the same meanings as described above].
Described specifically, Invention compound (1d) is available by hydrolyzing Compound (1c) (Compound (1b) wherein R4, R5=H, and Y=OAc) which has been synthesized by Process (B). This reaction is usually conducted in the presence of 1 to 3 equivalents, preferably 1 to 1.5 equivalents of a base at 20 to 40xc2x0 C., preferably 20 to 25xc2x0 C. for 1 to 5 hours. This reaction can be conducted in a water miscible solvent such as methanol, ethanol, dioxane or tetrahydrofuran. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate.
A salt of Invention Compound (1) is available, for example, by reacting Compound (1) with 1 to 2 equivalents, preferably 1 to 1.2 equivalents of an acid in an anhydrous solvent at 0 to 30xc2x0 C. for 0.1 to 0.5 hour. Preferred examples of the solvent include anhydrous ether, anhydrous tetrahydrofuran, anhydrous chloroform, anhydrous dioxane and anhydrous acetone. As the acid, the above-exemplified ones can be employed.
Invention compound (1) or salt thereof thus obtained can be purified by using ordinary methods such as column chromatography and recrystallization in combination.
Invention compound (I) or salt thereof exhibits excellent xcexc-opioid agonist action as described later in Tests and is therefore useful as a peripheral analgesic for animals including human being. The peripheral analgesic of the present invention can be used for the suppression or prevention of pain in various diseases (ex. various inflammatory diseases including arthritis and cancer), after operation, or in injury, fracture or burn.
Invention compound (1) or salt thereof, together with a pharmaceutically acceptable carrier, can be formed into a pharmaceutical composition of various dosage forms in a conventional manner. No particular limitation is imposed on the administration form and it can be selected as needed depending on the treating purpose. For example, administration can be conducted through any one of an orally dosable agent, injection, suppository, ointment and plaster. Such administration forms can each be manufactured in a manner known to those skilled in the art.
An orally dosable solid preparation such as tablet, coated tablet, granule, powder or capsule can be prepared by adding, to Invention compound (1), an excipient and if necessary, binder, disintegrator, lubricant, colorant, taste corrigent and smell corrigent and then treating the resulting mixture in a conventional manner.
An orally administrable liquid preparation such as a liquid preparation for internal use, syrup or elixir can be prepared by adding, to Invention compound (1), a taste corrigent, buffer, stabilizer or smell corrigent and then treating the resulting mixture in a conventional manner.
An injection such as subcutaneous, intramuscular or intravenous injection can be prepared by adding, to Invention compound (1), a pH regulator, buffer, stabilizer, isotonizing agent or local anesthetic agent and then treating the resulting mixture in a conventional manner.
A suppository can be prepared by adding, to Invention compound (1), a pharmaceutical carrier known to those skilled in the art, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglyceride and if necessary, a surfactant and then treating the resulting mixture in a conventional manner.
An ointment can be prepared by incorporating an ordinarily employed base material, stabilizer, humectant, preservative or the like as needed, and mixing them in a conventional manner.
A plaster may be prepared by applying the above-described ointment, or cream, gel, paste or the like, each made in a respective conventional manner, to an ordinarily employed backing material in a conventional manner.
The amount of Invention compound (1) to be incorporated in each of the above-described dosage forms differs depending on the conditions of the patient to be administered or the dosage form. In general, it is desired to incorporate it in an amount of about 0.25 to 100 mg for an orally dosable preparation, about 0.05 to 20 mg for an injection and about 0.1 to 50 mg for a suppository. The daily dose of the medicament in the above-described dosage form cannot be determined in a wholesale manner, because it differs with the symptom, body weight, age, sex, etc. of the patient. Usually, the daily dose may be about 0.005 to 2 mg/kg, preferably about 0.01 to 0.1 mg/kg per adult. It is desired to conduct administration once or in 2 to 4 portions a day.